Article

Does the use of recombinant AAV2 in pulmonary gene therapy damage lung function?

Laboratory of Cellular and Molecular Physiology, University of Rio de Janeiro, Centro de Ciências da Saúde, Ilha do Fundão, 21949-900 Rio de Janeiro, Brazil.
Respiratory Physiology & Neurobiology (impact factor: 2.24). 02/2008; 160(1):91-8. DOI:10.1016/j.resp.2007.09.002 pp.91-8
Source: PubMed

ABSTRACT Forty-eight BALB/c mice were divided into two groups of 24 animals each. In the control group (CTRL) saline was intratracheally instilled, while the virus group (VR) received rAAV2-GFP (4 x 10(9) particles). These groups were subdivided into four sub-groups (n=6). Pulmonary mechanical parameters were analyzed after 3 weeks (VR1d3w) and at 1 (VR2d1w), 2 (VR2d2w) and 3 weeks (VR2d3w) after a second AAV2 dose. Fractions of the area of alveolar collapse and the amount of polymorpho- and mononuclear cells were determined by point-counting technique. Viral transduction was evaluated by immunohistochemistry. Lung mechanical data were similar in all groups. However, there was an increase in airway and lung parenchyma cellularity and in the fraction of area of alveolar collapse in the VR2d2w group, which nonetheless decreased with time. There was no evidence of apoptosis in any group. In conclusion, the gene transfer vector AAV2 induces, in the lung, a discrete inflammatory reaction that does not affect either baseline lung mechanics or airway hyperresponsiveness.

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    Article: Intranasal delivery of T-bet modulates the profile of helper T cell immune responses in experimental asthma.
    S Y Wang, M Yang, X P Xu, G F Qiu, J Ma, S J Wang, X X Huang, H X Xu
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    ABSTRACT: Allergic asthma is caused by aberrant helper T (T(H)) type 2 immune responses in susceptible individuals, characterized by airway hyperresponsiveness, chronic airway inflammation, and mucus hypersecretion. Its prevalence continues to increase, but optimal treatment remains a challenge. The transcription factor T-bet is a master regulator of T(H)1 lineage commitment and strongly promotes interferon gamma expression during T(H)1 cell differentiation. The aim of this study was to explore the role of intranasal delivery of T-bet on the differentiation of T(H) cell subsets and airway inflammation in the ovalbumin (OVA)-induced mouse model of allergic airway inflammation. BALB/c mice were sensitized by intraperitoneal injection of OVA and challenged with nebulized OVA. Four days before the inhalation challenge, the sensitized mice were subjected to intranasal delivery of a recombinant adeno-associated virus vector carrying murine T-bet gene (AAV-T-bet). Expression of the transcription factors T-bet, GATA3, and Foxp3 was then assayed in the lungs, and airway histology was analyzed along with other inflammatory parameters, such as eosinophils and cytokines in bronchoalveolar lavage (BAL) fluid, and total and OVA-specific immunoglobulin (Ig) E in serum. Intranasal administration of AAV-T-bet efficiently balanced the T(H)1/T(H)2 transcription factor and cytokine profile and significantly decreased the number of eosinophils in BAL fluid. It also resulted in a reduction of peribronchial inflammation scores and serum IgE levels in OVA-sensitized and challenged mice during the effector phase. Our data show that intranasal delivery of T-bet can promote a T(H)1 immune response, restore a balanced Th immune response, and inhibit airway inflammation during the challenge phase in a mouse model of allergic airway inflammation.
    Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología 02/2008; 18(5):357-65. · 2.27 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

24 animals
 
3 weeks
 
alveolar collapse
 
baseline lung mechanics
 
control group
 
discrete inflammatory reaction
 
gene transfer vector AAV2 induces
 
Lung mechanical data
 
lung parenchyma cellularity
 
point-counting technique
 
polymorpho-
 
Pulmonary mechanical parameters
 
rAAV2-GFP
 
second AAV2 dose
 
Viral transduction
 
virus group
 
VR2d2w group
 

Roberta M Lassance